This invention relates to aminopyrimidinone compounds that are inhibitors of Interleukin receptor-associated kinases, in particular IRAK-4, and are useful in the treatment or prevention of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease.
Interleukin-1 receptor-associated kinases (IRAKs) are key components in the signal transduction pathways utilized by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), and Toll-like receptors (TLRs). Since TLRs initiate the first-wave of inflammatory signals and innate immune responses, they play a key role in many disease processes, including response to infections and auto-inflammatory disorders.
IRAK-4 belongs to a family of mammalian IRAKs that include IRAK-1, IRAK-2 and IRAK-M (also known as IRAK-3). IRAK-4 shares the domain structure of the other IRAKs and it is able to activate similar signal transduction pathways, namely NF-κB and MAPK pathways. It rapidly and transiently associates with IRAK-1 and TRAF6 in an IL-1-dependent manner but it is not functionally redundant with IRAK-1. Most strikingly, IRAK-4 is an active protein kinase and requires its kinase activity to activate NF-κB. Additionally, IRAK-4 might act upstream of IRAK-1 as an IRAK-1 activator. See Li, S. et al., “IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase,” Proc Natl Acad Sci USA. 2002 Apr. 16; 99(8):5567-72.
All four IRAK family members appear to play a role in Toll and IL-1R signaling. However, out of four members in the mammalian IRAK family, IRAK-4 is considered to be the “master IRAK”, the only family member indispensable for IL-1R/TLR signaling. Mouse knock-out studies have demonstrated the essential role for IRAK-4 in IL-1R, IL-18R and most TLR signaling (see, Suzuki, N, et al, “Severe impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4,” Nature, 2002, 416, 750-756). Furthermore, knock-in experiments by several groups have demonstrated that IRAK-4 requires its kinase activity for its function.
In humans, mutations resulting in IRAK-4 deficiency have been linked to susceptibility to bacterial infections, especially recurrent pyogenic bacterial infections (see, Picard, C., et al. “Pyogenic bacterial infections in humans with IRAK-4 deficiency.” Science, 2003, 299, 2076-2079). While IRAK-4 deficient children are susceptible to certain pyogenic infections, adults are not prone to chronic infections. It is possible that protective immunity remains sufficiently preserved to protect against infection while modulation of IRAK-4 function through kinase inhibition may tone down inflammatory response.
Given the important role of IRAK-4 in inflammatory processes, modulation of IRAK-4 kinase activity presents an attractive therapeutic approach for the treatment of immune and inflammatory diseases. The recent success in the determination of the 3-dimensional structure of the IRAK-4 kinase domain in complex with inhibitors has facilitated the understanding of the mechanistic role of IRAK-4 in immunity and inflammation as well as the development of specific IRAK-4 kinase inhibitors. See, Wang, et al, “IRAK-4 Inhibitors for Inflammation,” Current Topics in Medicinal Chemistry, 2009, 9, 724-737.
There exists a need in the art for small molecule compounds having desirable physiochemical properties as new therapeutic agents for treating or preventing inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease.